Assigned first to Destroyers, Scouting Force then to Destroyers, Battle Force, Perkins was homeported at San Diego and operated in the eastern Pacific prior to World War II. At Mare Island for overhaul, 7 December 1941, she reported for convoy escort duty on the 15th and on the 17th was enroute to Pearl Harbor. By 15 January 1942 she was back at Mare Island for the installation of new radar equipment and on the 25th she returned to Hawaii.

On 2 February she departed Pearl Harbor with Chicago for the southwest Pacific. On the 14th she joined Australian, New Zealand and other U.S. ships in the ANZAC Squadron then charged with protecting the eastern approaches to Australia and New Zealand. Through the spring, she continued operations with that squadron, steaming at times with fast carrier forces as they plied the Coral Sea to strike at enemy encroachments, escorting refueling units to rendezvous areas and screening larger ships of her own and combines forces as they blasted enemy positions from New Guinea to the Solomons.

On 1–2 May, the squadron joined with TF 11 and TF 17 then screened the carriers of those forces as their planes struck at Tulagi to open the Battle of the Coral Sea. Detached on the 7th, the squadron steamed to the Louisiade Archipelago to intercept a Japanese amphibious attack on Port Moresby via the Jomard Passage. That afternoon the ships were attacked by land based planes and in driving them off contributed to the diverting of the Japanese force, thus accomplishing the mission without engaging the enemy ships and setting the stage for the final action of the Battle of the Coral Sea the carrier battle on 8 May.

As the carrier forces fought to a draw, the ANZAC squadron continued to patrol to the southeast of Papua. On the 10th the squadron headed for Australia and for almost two months Perkins escorted convoys and patrolled off harbor entrances along that country’s Coral and Tasman Sea coasts. On 11 July she sailed for Auckland, thence to Nouméa. Convoy escort duty between Suva and New Caledonia followed and in mid-August she was forced back to New Zealand for propeller repairs. On the 20th, however, she sailed for Pearl Harbor where repairs were completed and additional radar equipment and 40mm guns were installed.

In mid-November Perkins headed west again, arriving at Espiritu Santo on the 27th. Three days later she departed Segond Channel in R.Adm. Wright’s cruiser-destroyer force to intercept and destroy enemy forces attempting to reinforce their units on Guadalcanal. At 2315, 5 radar contacts were made and a few minutes later the Battle of Tassafaronga was engaged. Perkins loosed 8 torpedoes, scoring none, and then turned her guns on the beach. Undamaged in the encounter she turned toward Tulagi to assist the burning Pensacola while Maury went to assist New Orleans. Continuing operations from Tulagi, she bombarded the Guadalcanal coast and served on escort assignments until January 1943. A brief availability at Nouméa followed and by the 13th she was back at Tulagi for further escort and support missions.

At the end of April Perkins joined TF 10 for tactical training and in May she returned to Australia to join the forces gathering for the thrust up the New Guinea coast to gain control of the Huon Peninsula. Into the summer the base at Milne Bay grew. At the end of June, Allied amphibious forces moved into Nassau Bay, just south of Salamaua, and into the Tobriands. Infantry units pressed toward Salamaua Australians from Wau in the foothills of the Owen Stanley Range and Americans from Nassau Bay. PT boats punched at the enemy’s Finschhafen-Lae supply line and A.A.F. and R.A.A.F. planes bombed and strafed Japanese installations as far as Wewak and Madang.

On 21 August Perkins, flagship of DesRon 5, led Smith, Conyngham and Mahan out of Milne Bay to make a sweep of Huon Gulf then bombard Finschhafen. On the night of 22–23 August they accomplished their mission and brought naval gunfire back to the New Guinea campaign after its absence through 18 months of ground fighting.

On 4 September Perkins bombarded the coast between the Bulu and Buso rivers, then covered Allied soldiers as they streamed ashore at Red Beach and headed toward Lae. On the 8th, she trained her guns on the isolated garrison at Lae and on the 15th the last remnants of that garrison pulled out. Salamaua, dependent on Lae, had already fallen and on the 16th Allied forces marched into Lae.

Finschhafen fell 2 October, the scouring of the river valleys commenced, and the increase in Allied traffic in Huon Gulf, together with the presence of Japanese submarines, brought Perkins back to escort duty. Reinforcements were escorted to Langemak Bay and to Scarlet Beach east of Satelberg. In November escort duties continued. Then, on the 28th, she departed Milne Bay for Buna, steaming independently. Shortly before 0200 on the 29th a dark image emerged from the blackness and a few minutes later the Australian troopship Duntroon rammed her on the portside, amidships. Splitting in two, Perkins went down and took four of her crew with her to a watery grave approximately two miles off Ipoteto Island.